NF-kappaB mediated miR-26a regulation in cardiac fibrosis Journal Article

Authors: Wei, C; Kim, I. K.; Kumar, S; Jayasinghe, S.; Hong, N.; Castoldi, G.; Catalucci, D.; Jones, W. K.; Gupta, S
Article Title: NF-kappaB mediated miR-26a regulation in cardiac fibrosis
Abstract: Micro-RNAs (miRNAs) are a class of small non-coding RNAs, recently emerged as a post-transcriptional regulator having a key role in various cardiac pathologies. Among them, cardiac fibrosis that occurs as a result from an imbalance of extracellular matrix proteins turnover and is a highly debilitating process that eventually lead to organ dysfunction. An emerging theme on is that miRNAs participate in feedback loop with transcription factors that regulate their transcription. NF-kappaB, a key transcription factor regulator controls a series of gene program in various cardiac diseases through positive and negative feedback mechanism. But, NF-kappaB mediated miRNA regulation in cardiac fibrosis remains obscure. Bioinformatics analysis revealed that miR-26a has targets collagen I and CTGF and possesses putative NF-kappaB binding element in its promoter region. Here, we show that inhibition of NF-kappaB in cardiac fibroblast restores miR-26a expression, attenuating collagen I, and CTGF gene expression in the presence of Ang II, conferring a feedback regulatory mechanism in cardiac fibrosis. The target genes for miR-26a were confirmed using 3'-UTR luciferase reporter assays for collagen I and CTGF genes. Using NF-kappaB reporter assays, we determine that miR-26a overexpression inhibits NF-kappaB activity. Finally, we show that miR-26a expression is restored along with the attenuation of collagen I and CTGF genes in cardiac specific IkBa triple mutant transgenic mice (preventing NF-kappaB activation) subjected to 4 weeks transverse aortic banding (TAC), compared to wild type (WT) mice. The data indicate a potential role of miR-26a in cardiac fibrosis and, offer novel therapeutic intervention.
Journal Title: Journal of cellular physiology
Volume: 228
Issue: 7
ISSN: 1097-4652; 0021-9541
Publisher: Wiley Periodicals, Inc  
Journal Place: United States
Date Published: 2013
Start Page: 1433
End Page: 1442
Language: eng
Notes: CI: Copyright (c) 2012; JID: 0050222; 0 (Collagen Type I); 0 (Ctgf protein, mouse); 0 (Ctgf protein, rat); 0 (I-kappa B Proteins); 0 (MIRN26 microRNA, rat); 0 (MicroRNAs); 0 (Mirn26 microRNA, mouse); 0 (Mutant Proteins); 0 (NF-kappa B); 0 (RNA, Messenger); 11128-99-7 (Angiotensin II); 139568-91-5 (Connective Tissue Growth Factor); 139874-52-5 (NF-kappaB inhibitor alpha); 2012/10/08 [received]; 2012/11/27 [accepted]; ppublish